Angiogenesis is a fundamental process by which new blood vessels are formed through sprouting, branching, proliferation, and tubule formation by endothelial cells from existing vasculature. In healthy humans, this neovascularization is under stringent control, normally occurring only during embryonic development, endometrial regulation, breast lactation and wound repair. However, in many pathological conditions, such as rheumatoid arthritis, solid tumors, Kaposi's sarcoma, blindness due to ocular neovascularization, psoriasis and atherosclerosis, disease progression is dependent upon persistent angiogenesis. The vasculature, which is the conduit for drug delivery, is one of the most accessible tissues in the body. Each endothelial cell of tumor vessels is estimated to support 100 to 1,000 neighboring cells, yet in the absence of an angiogenic stimulus endothelial cells typically divide only once every thousand days.
A number of polypeptide growth factors and their associated endothelial cell specific receptors have been discovered which are primarily responsible for the stimulation of endothelial cell growth, differentiation and the establishment of new vasculature. These growth factor receptors include the vascular endothelial growth factor receptors (VEGFR) Flk-1 (mouse), KDR/VEG-FR-2 (human), Flt-1/VEGFR-1, and Flt-4/VEGFR-3. Receptors which are responsible for neovascularizaton also include the receptor tyrosine kinases Tie-1 and Tie-2.
Due to its role in regulating new vascular development, Tie-2 is a potential target for therapies aimed at controlling diseases which depend upon persistent angiogenesis. The development of biochemical assays for Tie-2 has enabled drug discovery to proceed along the pathways of identifying lead Tie-2 inhibitors by high-throughput screening of compound libraries and by testing compounds that mimic substrate structure; however, rational, structure-based design has not been possible up to this point because of the lack of accurate three-dimensional structural data for Tie-2 receptors.